Contact system activation in human sepsis - 47kD HK, a marker of sepsis severity?

AIM: This pilot study seeks to determine whether contact system activation (CSA) occurs in human sepsis patients and to characterise blood levels of the 47kD light chain of high-molecular weight kininogen (47kD HK). METHODS: Six consecutive patients with clinical suspicion of sepsis were evaluated on days 1, 2, 3 and 6-8 for 47kD HK blood levels expressed in U/ml of whole blood and as percent of total HK. 47kD HK was measured in whole blood by quantitative immunoblot analysis. RESULTS: On study day 1 or 2, analysis of 47kD HK in U/ml of whole blood identified CSA in 3/6 patients.When 47kD HK levels were expressed as percent of total HK, 4/6 patients were identified with CSA before day 3. The degree of CSA as assayed by the presence of 47kD HK correlated with the severity of the systemic inflammatory syndrome (SIRS), i.e. mean CSA increased progressively from basal levels in healthy controls (0.08 U/ml or 10.4%) to patients without SIRS (0.10 U/ml or 15.1%), to patients with sepsis (0.12 U/ml or 15.0%), and finally to patients in a combined category of severe sepsis and septic shock (0.13 U/ml or 17.4%). CONCLUSION: CSA, defined by increased 47kD HK, occurred early on in the course of sepsis in a subset of sepsis patients. 47kD HK levels, an indicator of bradykinin release, correlated with sepsis severity. Future larger studies will need to evaluate the role of 47kD HK as a biomarker for both prognosis and treatment response in human sepsis..

Allergic bronchopulmonary aspergillosis: the hunt for a diagnostic serological marker in cystic fibrosis patients

The diagnosis of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis patients remains challenging, mainly owing to overlapping symptoms of the underlying lung disease with clinical symptoms of ABPA. In addition, a varying mixture of diagnostic criteria, including clinical status, radiological findings and immunological measurements, has led to confusion and differing recommendations. In order to help simplify as well as standardize the diagnostic criteria for ABPA, different serological markers have been evaluated in the last 20 years and their usefulness has been assessed in many clinical studies. This review presents current diagnostic criteria of ABPA, with a special focus on serum markers supporting the diagnosis and explains why the hunt for a serological marker for ABPA is still ongoing.

CD69 upregulation on T cells as an in vitro marker for delayed-type drug hypersensitivity

BACKGROUND: T cells play a key role in delayed-type drug hypersensitivity reactions. Their reactivity can be assessed by their proliferation in response to the drug in the lymphocyte transformation test (LTT). However, the LTT imposes limitations in terms of practicability, and an alternative method that is easier to implement than the LTT would be desirable. METHODS: Four months to 12 years after acute drug hypersensitivity reactions, CD69 upregulation on T cells of 15 patients and five healthy controls was analyzed by flow cytometry. RESULTS: All 15 LTT-positive patients showed a significant increase of CD69 expression on T cells after 48 h of drug-stimulation exclusively with the drugs incriminated in drug-hypersensitivities. A stimulation index of 2 as cut-off value allowed discrimination between nonreactive and reactive T cells in LTT and CD69 upregulation. T cells (0.5-3%) showed CD69 up-regulation. The reactive cell population consisted of a minority of truly drug reactive T cells secreting cytokines and a higher number of bystander T cells activated by IL-2 and possibly other cytokines. CONCLUSIONS: CD69 upregulation was observed after 2 days in all patients with a positive LTT after 6 days, thus appearing to be a promising tool to identify drug-reactive T cells in the peripheral blood of patients with drug-hypersensitivity reactions.

Statistical methods for multi-marker testing in genetic association studies

As the development of genotyping and next-generation sequencing technologies, multi-marker testing in genome-wide association study and rare variant association study became active research areas in statistical genetics. This dissertation contains three methodologies for association study by exploring different genetic data features and demonstrates how to use those methods to test genetic association hypothesis. The methods can be categorized into in three scenarios: 1) multi-marker testing for strong Linkage Disequilibrium regions, 2) multi-marker testing for family-based association studies, 3) multi-marker testing for rare variant association study. I also discussed the advantage of using these methods and demonstrated its power by simulation studies and applications to real genetic data.

Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies

BACKGROUND/AIMS: The integrin alphavbeta6 promotes proliferation of specialized epithelia and acts as a receptor for the activation of latent TGFbeta1. We studied alphavbeta6 expression in experimental and human liver fibrosis and the potential of its pharmacological inhibition for treatment of hepatic fibrosis. METHODS: alphavbeta6 expression was studied by quantitative PCR and immunohistochemistry in rats with cirrhosis due to bile duct ligation (BDL), administration of thioacetamide (TAA), in Mdr2(Abcb4)(-/-) mice with spontaneous biliary fibrosis, and in livers of patients with chronic hepatitis C (n=79) and end-stage liver disease due to various etiologies (n=18). The effect of a selective alphavbeta6 inhibitor was evaluated in Mdr2(Abcb4)(-/-) mice with ongoing fibrogenesis. RESULTS: Integrin beta6 mRNA increased with fibrosis stage in hepatitis C and was upregulated between 25- and 100-fold in TAA- and BDL-induced cirrhosis, in Mdr2(Abcb4)(-/-) mice and in human end-stage liver disease. alphavbeta6 protein was absent in normal livers and expressed de novo on (activated) bile duct epithelia and transitional hepatocytes. A single dose of the alphavbeta6 inhibitor injected into Mdr2(Abcb4)(-/-) mice significantly induced profibrolytic matrix metalloproteinases (MMP)-8 and -9 after 3 h, with a corresponding increase in extracellular matrix-degrading activities. In parallel profibrogenic transcripts (procollagen alpha1(I), TGFbeta2, and MMP-2) showed a trend of downregulation. CONCLUSIONS: (1) Integrin alphavbeta6 is induced de novo in rodent and human liver fibrosis, where it is expressed on activated bile duct epithelia and (transitional) hepatocytes during fibrosis progression. (2) In vivo a single dose of a small molecule alphavbeta6 inhibitor induced antifibrogenic and profibrolytic genes and activities, suggesting alphavbeta6 is a unique target for treatment of liver fibrosis.

[Complementary and alternative medicine in primary care in Switzerland]

OBJECTIVE: This study investigated the current supply of complementary and alternative medicine (CAM) in Swiss primary care. Information was collected on physicians' qualifications in CAM, frequency of patients' demand for CAM, physicians' supply and temporal resources for CAM as well as physicians' referrals to CAM. MATERIAL AND METHODS: 750 (500 German-speaking and 250 French-speaking) randomly selected Swiss female and male primary care physicians were asked to complete a questionnaire (response rate 50.4%). Sociodemographic data on professional training, place of residence, and sex were used to calculate a weighting factor to correct the responders' data in the analysis accordingly. RESULTS: 14.2% of the physicians were qualified in at least one CAM discipline. Around 30% (95% confidence interval 25.4-34.6%) of the physicians were asked for CAM by their patients more than once a week. Homeopathy and phytotherapy were the most frequently offered therapies, followed by traditional Chinese medicine (TCM)/acupuncture. 62.5% (57.6-67.4%) of the physicians refer their patients to CAM. Most patients were referred to TCM/acupuncture. Of the 37.2% (32.6-42.4%) of the physicians who do not refer their patients to CAM, around 40% (35.1-44.9%) offer it themselves. CONCLUSION: About three quarters of the physicians offer CAM themselves or refer their patients to CAM treatments. CAM is very important in primary medical care in Switzerland. Clear regulations for CAM are required in order to ensure a high quality in care.

Circulating plasma surfactant protein type B as biological marker of alveolar-capillary barrier damage in chronic heart failure

BACKGROUND: Surfactant protein type B (SPB) is needed for alveolar gas exchange. SPB is increased in the plasma of patients with heart failure (HF), with a concentration that is higher when HF severity is highest. The aim of this study was to evaluate the relationship between plasma SPB and both alveolar-capillary diffusion at rest and ventilation versus carbon dioxide production during exercise. METHODS AND RESULTS: Eighty patients with chronic HF and 20 healthy controls were evaluated consecutively, but the required quality for procedures was only reached by 71 patients with HF and 19 healthy controls. Each subject underwent pulmonary function measurements, including lung diffusion for carbon monoxide and membrane diffusion capacity, and maximal cardiopulmonary exercise test. Plasma SPB was measured by immunoblotting. In patients with HF, SPB values were higher (4.5 [11.1] versus 1.6 [2.9], P=0.0006, median and 25th to 75th interquartile), whereas lung diffusion for carbon monoxide (19.7+/-4.5 versus 24.6+/-6.8 mL/mm Hg per min, P<0.0001, mean+/-SD) and membrane diffusion capacity (28.9+/-7.4 versus 38.7+/-14.8, P<0.0001) were lower. Peak oxygen consumption and ventilation/carbon dioxide production slope were 16.2+/-4.3 versus 26.8+/-6.2 mL/kg per min (P<0.0001) and 29.7+/-5.9 and 24.5+/-3.2 (P<0.0001) in HF and controls, respectively. In the HF population, univariate analysis showed a significant relationship between plasma SPB and lung diffusion for carbon monoxide, membrane diffusion capacity, peak oxygen consumption, and ventilation/carbon dioxide production slope (P<0.0001 for all). On multivariable logistic regression analysis, membrane diffusion capacity (beta, -0.54; SE, 0.018; P<0.0001), peak oxygen consumption (beta, -0.53; SE, 0.036; P=0.004), and ventilation/carbon dioxide production slope (beta, 0.25; SE, 0.026; P=0.034) were independently associated with SPB. CONCLUSIONS: Circulating plasma SPB levels are related to alveolar gas diffusion, overall exercise performance, and efficiency of ventilation showing a link between alveolar-capillary barrier damage, gas exchange abnormalities, and exercise performance in HF.

Long-term gas exchange characteristics as marker of deterioration in patients with cystic fibrosis

Background and Aim In patients with cystic fibrosis (CF) the architecture of the developing lungs and the ventilation of lung units are progressively affected, influencing intrapulmonary gas mixing and gas exchange. We examined the long-term course of blood gas measurements in relation to characteristics of lung function and the influence of different CFTR genotype upon this process. Methods Serial annual measurements of PaO2 and PaCO2 assessed in relation to lung function, providing functional residual capacity (FRCpleth), lung clearance index (LCI), trapped gas (VTG), airway resistance (sReff), and forced expiratory indices (FEV1, FEF50), were collected in 178 children (88 males; 90 females) with CF, over an age range of 5 to 18 years. Linear mixed model analysis and binary logistic regression analysis were used to define predominant lung function parameters influencing oxygenation and carbon dioxide elimination. Results PaO2 decreased linearly from age 5 to 18 years, and was mainly associated with FRCpleth, (p < 0.0001), FEV1 (p < 0.001), FEF50 (p < 0.002), and LCI (p < 0.002), indicating that oxygenation was associated with the degree of pulmonary hyperinflation, ventilation inhomogeneities and impeded airway function. PaCO2 showed a transitory phase of low PaCO2 values, mainly during the age range of 5 to 12 years. Both PaO2 and PaCO2 presented with different progression slopes within specific CFTR genotypes. Conclusion In the long-term evaluation of gas exchange characteristics, an association with different lung function patterns was found and was closely related to specific genotypes. Early examination of blood gases may reveal hypocarbia, presumably reflecting compensatory mechanisms to improve oxygenation.

[Role of complementary medicine in type 1 diabetes mellitus in two Swiss centres]

Insulin replacement is the only effective treatment of type 1 Diabetes mellitus (T1DM). Nevertheless, many complementary treatments are in use for T1DM. In this study we assessed by questionnaire that out of 342 patients with T1DM, 48 (14%; 13.4% adult, 18.5% paediatric; 20 male, 28 female) used complementary medicine (CM) in addition to their insulin therapy. The purpose of the use of CM was to improve general well-being, ameliorate glucose homeostasis, reduce blood glucose levels as well as insulin doses, improve physical fitness, reduce the frequency of hypoglycaemia, and control appetite. The modalities most frequently used are cinnamon, homeopathy, magnesium and special beverages (mainly teas). Thus, good collaboration between health care professionals will allow optimal patient care.